Christian Sorg

Selective changes of resting-state networks in individuals at risk for Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative disorder that prominently affects cerebral connectivity. Assessing the functional connectivity at rest, recent functional MRI (fMRI) studies reported on the existence of resting-state networks (RSNs). RSNs are characterized by spatially coherent, spontaneous fluctuations in the blood oxygen level-dependent signal and are made up of regional patterns commonly involved in functions such as sensory, attention, or default mode processing. In AD, the default mode network (DMN) is affected by reduced functional connectivity and atrophy. In this work, we analyzed functional and structural MRI data from healthy elderly (n = 16) and patients with amnestic mild cognitive impairment (aMCI) (n = 24), a syndrome of high risk for developing AD. Two questions were addressed: (i) Are any RSNs altered in aMCI? (ii) Do changes in functional connectivity relate to possible structural changes? Independent component analysis of resting-state fMRI data identified eight spatially consistent RSNs. Only selected areas of the DMN and the executive attention network demonstrated reduced network-related activity in the patient group. Voxel-based morphometry revealed atrophy in both medial temporal lobes (MTL) of the patients. The functional connectivity between both hippocampi in the MTLs and the posterior cingulate of the DMN was present in healthy controls but absent in patients. We conclude that in individuals at risk for AD, a specific subset of RSNs is altered, likely representing effects of ongoing early neurodegeneration. We interpret our finding as a proof of principle, demonstrating that functional brain disorders can be characterized by functional-disconnectivity profiles of RSNs.

Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease

Objective: To examine the influence of the APOE genotype on levels of β-amyloid (Aβ) plaque load and atrophy in patients with Alzheimer disease (AD) in vivo. Methods: Thirty-two patients with moderate AD were divided into carriers and noncarriers of the ε4 allele. These groups were matched for age, disease duration, education, and cognitive impairment. In all subjects, [11C]PIB-PET was performed for measurement of cerebral Aβ plaque deposition and cranial MRI for the assessment of gray matter volume by voxel-based morphometry (VBM) and for correction of partial volume effects (PVE) in the PET data. Voxel-based comparisons (SPM5) were performed between patient groups and healthy control populations and completed with multiple regression analyses between imaging data and ε4 allele frequency. Results: Compared to controls, AD-typical patterns of [11C]PIB retention and atrophy were detected in both ε4-positive and ε4-negative patient groups. In direct comparison, significantly stronger and more extended [11C]PIB uptake was found in ε4-positive patients in bilateral temporoparietal and frontal cortex, surviving PVE correction. VBM analysis demonstrated comparable levels of atrophy in both patient groups. Regression analyses revealed a linear association between higher ε4 allele frequency and stronger temporoparietal Aβ plaque deposition, independently of other confounds. No major correlation between ε4 allele frequency and gray matter decrease was observed. Conclusion: These results indicate that the ε4-positive APOE genotype not only represents a risk factor for Alzheimer disease (AD), but also results in higher levels of Aβ plaque deposition in ε4-positive patients with AD compared to age-matched ε4-negative patients with similar levels of cognitive impairment and brain atrophy. The potential role of Aβ plaque imaging for patient inclusion and follow-up in anti-amyloid therapy trials is strengthened by these findings.

Altered cerebral response to noxious heat stimulation in patients with somatoform pain disorder.

&NA; Idiopathic chronic pain conditions with a mismatch between anatomical abnormalities and symptoms can be categorized as somatoform pain disorder according to the DSM‐IV criteria. A dysfunction of pain processing circuits has been suggested as one underlying pathophysiological factor. There is accumulating evidence for a crucial role of affect regulating brain structures such as the medial frontal cortex in this context. We investigated the cerebral processing of noxious heat stimuli as objective marker for pain sensation in 12 right handed women with somatoform pain disorder fulfilling DSM‐IV criteria and 13 age‐matched healthy volunteers using functional MRI. The average ratings for experimentally induced pain were not significantly different between controls and patients concerning pain intensity and pain unpleasantness. Comparing patients with controls a pain related hypoactive state of the ventromedial prefrontal/orbitofrontal cortex (BA 10/11) and a hyperactive state of the parahippocampal gyrus, amygdala and anterior insula were found in the patient group. Our findings of an altered cerebral processing of experimentally induced pain in patients with somatoform pain disorder support the hypothesis of dysfunctional pain processing, especially in affect regulating regions.

Patients with pain disorder show gray-matter loss in pain-processing structures: a voxel-based morphometric study.

Objective: To investigate whether the functional changes in pain disorder might be reflected by structural brain changes. Pain disorder assessed with the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria is characterized by persistent and distressing chronic pain at one or more body sites which cannot be fully explained by a physiological process or somatic disorder. Psychological factors are thought to play a major role. Recent neuroimaging studies evidenced altered pain processing in patients suffering from this disorder. Methods: Fourteen right-handed women fulfilling the DSM-IV criteria for pain disorder and 25 healthy age-matched women were investigated with magnetic resonance imaging. In the voxel-based morphometry analysis, we compared both groups for changes of gray-matter density. We included age and Beck Depression Inventory scores as nuisance variables to minimize possible confounding effects of age or depressive comorbidity. Results: In the patient group, we found significant gray-matter decreases in the prefrontal, cingulate, and insular cortex. These regions are known to be critically involved in the modulation of subjective pain experiences. Conclusions: In the context of similar results in patients with other functional pain syndromes, such as fibromyalgia and chronic back pain, we suggest that structural changes in fronto-limbic brain circuits represent not only an objective marker of these pain syndromes but also constitute a critical pathophysiological element. These findings represent a further proof of the important role of central changes in pain disorder. DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; ICD-10 = International Statistical Classification of Diseases and Related Health Problems, 10th Revision; VBM = voxel-based morphometry; fMRI = functional magnetic resonance imaging; GM = gray matter; WM = white matter; CSF = cerebrospinal fluid; BDI = Beck Depression Inventory; MNI = standardized reference space defined by the Montreal Neurological Institute; SOMS = screening for somatoform symptoms; PPS = Pain Perception Scale; SCID = Structured Clinical Interview for DSM-IV disorders.

Cognitive rehabilitation in patients with mild cognitive impairment

To explore the benefits of a multi‐component cognitive rehabilitation programme in patients with mild cognitive impairment (MCI).

Increased Intrinsic Brain Activity in the Striatum Reflects Symptom Dimensions in Schizophrenia

Striatal dysfunction is thought to be a fundamental element in schizophrenia. Striatal dopamine dysfunction impacts on reward processing and learning and is present even at rest. Here, we addressed the question whether and how spontaneous neuronal activity in the striatum is altered in schizophrenia. We therefore assessed intrinsic striatal activity and its relation with disorder states and symptom dimensions in patients with schizophrenia. We performed resting-state functional (rs-fMRI) and structural magnetic resonance imaging as well as psychometric assessment in 21 schizophrenic patients during psychosis. On average 9 months later, we acquired follow-up data during psychotic remission and with comparable levels of antipsychotic medication. Twenty-one age- and sex-matched healthy controls were included in the study. Independent component analysis of fMRI data yielded spatial maps and time-courses of coherent ongoing blood-oxygen-level-dependent signal fluctuations, which were used for group comparisons and correlation analyses with scores of the positive and negative syndrome scale. During psychosis, coherent intrinsic activity of the striatum was increased in the dorsal part and correlated with positive symptoms such as delusion and hallucination. In psychotic remission of the same patients, activity of the ventral striatum was increased and correlated with negative symptoms such as emotional withdrawal and blunted affect. Results were controlled for volumetric and medication effects. These data provide first evidence that in schizophrenia intrinsic activity is changed in the striatum and corresponds to disorder states and symptom dimensions.

Aberrant topology of striatum's connectivity is associated with the number of episodes in depression

In major depressive disorder, depressive episodes reoccur in ∼60% of cases; however, neural mechanisms of depressive relapse are poorly understood. Depressive episodes are characterized by aberrant topology of the brains intrinsic functional connectivity network, and the number of episodes is one of the most important predictors for depressive relapse. In this study we hypothesized that specific changes of the topology of intrinsic connectivity interact with the course of episodes in recurrent depressive disorder. To address this hypothesis, we investigated which changes of connectivity topology are associated with the number of episodes in patients, independently of current symptoms and disease duration. Fifty subjects were recruited including 25 depressive patients (two to 10 episodes) and 25 gender- and age-matched control subjects. Resting-state functional magnetic resonance imaging, Harvard-Oxford brain atlas, wavelet-transformation of atlas-shaped regional time-series, and their pairwise Pearsons correlation were used to define individual connectivity matrices. Matrices were analysed by graph-based methods, resulting in outcome measures that were used as surrogates of intrinsic network topology. Topological scores were subsequently compared across groups, and, for patients only, related with the number of depressive episodes and current symptoms by partial correlation analysis. Concerning the whole brain connectivity network of patients, small-world topology was preserved but global efficiency was reduced and global betweenness-centrality increased. Aberrant nodal efficiency and centrality of regional connectivity was found in the dorsal striatum, inferior frontal and orbitofrontal cortex as well as in the occipital and somatosensory cortex. Inferior frontal changes were associated with current symptoms, whereas aberrant right putamen network topology was associated with the number of episodes. Results were controlled for effects of total grey matter volume, medication, and total disease duration. This finding provides first evidence that in major depressive disorder aberrant topology of the right putamens intrinsic connectivity pattern is associated with the course of depressive episodes, independently of current symptoms, medication status and disease duration. Data suggest that the reorganization of striatal connectivity may interact with the course of episodes in depression thereby contributing to depressive relapse risk.

Local activity determines functional connectivity in the resting human brain: a simultaneous FDG-PET/fMRI study.

Over the last decade, synchronized resting-state fluctuations of blood oxygenation level-dependent (BOLD) signals between remote brain areas [so-called BOLD resting-state functional connectivity (rs-FC)] have gained enormous relevance in systems and clinical neuroscience. However, the neural underpinnings of rs-FC are still incompletely understood. Using simultaneous positron emission tomography/magnetic resonance imaging we here directly investigated the relationship between rs-FC and local neuronal activity in humans. Computational models suggest a mechanistic link between the dynamics of local neuronal activity and the functional coupling among distributed brain regions. Therefore, we hypothesized that the local activity (LA) of a region at rest determines its rs-FC. To test this hypothesis, we simultaneously measured both LA (glucose metabolism) and rs-FC (via synchronized BOLD fluctuations) during conditions of eyes closed or eyes open. During eyes open, LA increased in the visual system, and the salience network (i.e., cingulate and insular cortices) and the pattern of elevated LA coincided almost exactly with the spatial pattern of increased rs-FC. Specifically, the voxelwise regional profile of LA in these areas strongly correlated with the regional pattern of rs-FC among the same regions (e.g., LA in primary visual cortex accounts for ∼50%, and LA in anterior cingulate accounts for ∼20% of rs-FC with the visual system). These data provide the first direct evidence in humans that local neuronal activity determines BOLD FC at rest. Beyond its relevance for the neuronal basis of coherent BOLD signal fluctuations, our procedure may translate into clinical research particularly to investigate potentially aberrant links between local dynamics and remote functional coupling in patients with neuropsychiatric disorders.

Impact of Alzheimers Disease on the Functional Connectivity of Spontaneous Brain Activity

Alzheimers disease (AD) prominently affects the structure and function of cerebral networks. Reflecting the complex network structure of the brain, spontaneous brain activity is organized by synchronized activity across distinct temporal and spatial scales. Temporal correlations of the functional MRI (fMRI) signal during rest have been used to characterize the impact of AD on the functional connectivity of spontaneous brain activity. Here we review studies using resting-state fMRI (rs-fMRI) to explore AD-induced changes of synchronized intrinsic activity at three levels of brain organization: the regional, inter-regional and large-scale level. Changes in posterior areas of the default network (DN) and the medial temporal lobes seem to be central to AD. These areas show remarkable disturbances in neuronal communication at all spatial levels and in very early stages of the disease. Finally, rs-fMRI seems to have the potential to produce connectivity-related biomarkers that distinguish AD and healthy aging.

Progression of cerebral amyloid load is associated with the apolipoprotein E ε4 genotype in Alzheimer's disease.

BACKGROUND Pittsburgh Compound B ([¹¹C] PiB) is a specific positron emission tomography (PET) marker of cerebral amyloid deposits. Only few data have been published on in vivo longitudinal changes of amyloid load in Alzheimers disease (AD) patients, with conflicting results. Therefore, little is known about the factors that influence these changes. METHODS A group of 24 patients with probable AD diagnosed by combining established clinical criteria with an AD-typical pattern in [(18)F] fluoro-deoxy-glucose PET underwent [¹¹C] PiB-PET examinations at baseline and after 24 months. The difference of amyloid load between the two examinations and the association with clinical and neurobiological variables was examined with a regions-of-interest approach and voxel-based analyses. RESULTS Cerebral [¹¹C] PiB uptake ratio increased significantly by an annual rate of 3.92%. Although the increase occurred in all parts of the neocortex, no increase was detected in the archipallium. The increase was gene-dose-dependent (analysis of variance p = .012) to the number of apolipoprotein E ε4 alleles. Progression of dementia symptoms was correlated to the [¹¹C] PiB increase in numerous regions associated with cognition. CONCLUSIONS The results of this study indicate that a significant increase of amyloid deposition occurs in patients with AD during a relatively short interval of its clinical course. The rate of amyloid aggregation rate is closely associated with the apolipoprotein E genotype, which might be important for the evaluation of antiamyloid drug treatment effects. The present study further emphasizes the value of amyloid-plaque imaging as a marker of disease progression and as a potential surrogate marker to be used in antiamyloid drug trials.